Role of the angiotensin II AT2-subtype receptors in the blood pressure-lowering effect of losartan in salt-restricted rats

Objective. The aim of this study was to evaluate the potential role of the angiotensin II (Ang II) AT₂ receptors (AT₂) in the control of blood pressure (BP) in the rat and the effects of AT₂ receptors on BP during AT₁ receptor (AT₁) antagonism. Methods. The study was performed in 52 Sprague-Dawley rats, which were preliminarily salt-restricted (SR) to enhance circulating and tissue renin-angiotensin system activity. To explore whether AT₂ plays a role in BP regulation, the BP effects of the selective AT₂ and AT₁ receptor antagonists PD123319 (PD) (50 μg/kg/min) and losartan (Los) (10 mg/kg/day), were studied. Seven rats were used as a control group. To define whether AT₂ plays a role in the BP response observed during AT₁ antagonism, 17 Los treated rats were divided into two groups: seven were treated with both antagonists (Los + PD) and 10 rats received Los + vehicle. The effects of both drugs were also studied in bilaterally nephrectomized rats (NX). All treatments were maintained for 1 week. Results. Los reduced BP significantly in both intact (P <0.001) and NX (P <0.05) rats, while PD increased BP in intact and NX rats (both P <0.001). In the Los + PD group BP levels were significantly higher (P <0.001 vs Los and Los + vehicle, P = ns vs pretreatment), while vehicle infusion did not modify the BP response to Los. Conclusion. The results show that in salt-restricted rats AT₂ blockade offsets the BP-lowering effect of losartan and suggest that AT₂ receptors contribute to the hypotensive effects of losartan. Thus, AT₁ receptor antagonists such as losartan, which are becoming widely used in the clinical treatment of hypertension, may reduce BP not only by blockade of AT₁ receptors, but also through the stimulation of AT₂ receptors by the excess of angiotensin II.